Piezoelectric devices are used in various detector systems, e.g., to detect the presence of specifically adsorbed materials on a surface or to detect the coagulation state of a protein solution. However, many of these designs are difficult or expensive to manufacture, or are not compatible with at a micro-scale designs for testing of very small samples.
Various techniques have been used over the years to determine the coagulation status of blood. The standard for coagulation determinations in medical technology for some time was the fibrometer, which detects coagulation directly with a mechanical probe. Recently, devices have been introduced that detect changes in the coagulation status of blood or plasma indirectly by measuring changes in optical or electrical characteristics of the fluid with time. However, there is a need for a microscale device that directly measures physical parameters, e.g., of clotting blood.
A fibrometer is a device with a heat block to condition the temperature of a sample to be tested, a timer, and a mechanical probe that moves in the sample to detect when a clot has formed. A couple of drops of citrate anti-coagulated plasma is held in the heat block with the probe positioned above. At the instant a technician injects a coagulant into the plasma he presses a button that starts a timer and drops the moving probe down into the plasma. The timer stops at the time when the plasma becomes coagulated enough to stop the probe from moving. Of course, one can see that precision of this assay can vary significantly depending on the skill of the technician. In addition the required sample size can be excessive, especially considering the required redundant and confirmatory retesting.
A macro-scale device and method for performing blood coagulation assays is described in Wu, et al. (U.S. Pat. No. 6,200,532). Devices for performing prothrombin times and activated partial thromboplastin times and other clotting parameters are disclosed. The devices include, e.g., a disposable cartridge containing a sample inlet for sample delivery, a capillary channel to provide fluid flow, a reaction chamber with an appropriate dry reagent for a specific assay, a magnetic bender, and a piezoelectric sensor. The magnetic bender is driven by an electromagnetic field generator and is attached onto a piezoelectric film sensor in contact with a blood sample. Electric signals (voltages) generated at the piezo film are detected by a detector circuit and characterized by frequency and amplitude. The voltages from the piezo film can be correlated to a biochemical reaction in the reaction chamber. For example, blood coagulation can be detected as reduced amplitude signals from the piezo sensor as the solidifying clot reduces freedom of piezo film movement. However, such a device is hard to manufacture and operate at a micro-scale.
In Meller (U.S. Pat. No. 5,892,144), a biosensor is provided for measuring changes in viscosity, density and/or mass in a fluid. The piezoelectric element is a disk of piezoelectric film in a chamber. According to the invention, the reagents necessary for the test are contained in a support matrix in contact with a measurement surface of a piezoelectric element. An oscillator vibrates the piezo disk and density of a sample in contact with the disk can be determined by an evaluation circuit. Such a device requires direct contact of the sample with the piezo film and its associated electrodes, or provision of additional insulator layers that can interfere with the sensitivity of the device. The mass of the sensor (typically, a quartz crystal) relative to the sample can also reduce the sensitivity of the device.
In view of the above, a need exists for a microscale device that automates coagulation assay steps. It would be desirable to measure a sample viscosity without direct contact of sample with electrically energized system components. It would be beneficial to have micro-scale and signal enhancing designs to reduce sample size and enhance assay sensitivity. The present invention provides these and other features that will be apparent upon review of the following.